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Citation for the original published paper (version of record):
Vears, D F., Niemiec, E., Howard, H C., Borry, P. (2018)Analysis of VUS reporting, variant reinterpretation and recontact policies in clinicalgenomic sequencing consent formsEuropean Journal of Human Genetics, 26(12): 1743-1751https://doi.org/10.1038/s41431-018-0239-7
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1
Analysis of VUS reporting, variant reinterpretation and recontact policies in
clinical genomic sequencing consent forms
Running title: VUS reporting, reinterpretation and recontact
Danya F. Vears PhD 1, 2, Emilia Niemiec3, 4, 5, 6, Heidi Carmen Howard PhD 6 & Pascal
Borry PhD 1, 2
1 Centre for Biomedical Ethics and Law, Department of Public Health and Primary Care, KU Leuven, Kapucijnenvoer 35 Box 7001, 3000 Leuven, Belgium.
2 Leuven Institute for Human Genomics and Society, 3000 Leuven, Belgium. 3Erasmus Mundus Joint International Doctoral (Ph.D.) Degree Programme in Law, Science and Technology, University of Bologna, Via Galliera 3, 40121 Bologna, Italy.
4 Department of Law, University of Turin, Lungo Dora Siena 100 A, 10153 Turin, Italy. 5 Centre for Ethics and Law in the Life Sciences, Leibniz University Hannover, Am Klagesmarkt 14-17, 30159 Hannover, Germany.
6 Centre for Research Ethics and Bioethics, Uppsala University, Box 564, SE-751 22, Uppsala, Sweden.
Corresponding author:
Danya F Vears
Center for Biomedical Ethics and Law
Department of Public Health and Primary Care
KU Leuven
Kapucijnenvoer 35, Box 7001
3000 Leuven
Belgium
Phone: +32 16 37 46 85
Fax: +32 16 33 69 52
Email: [email protected]
2
Abstract
There are several key unsolved issues relating to the clinical use of next generation
sequencing, such as: should laboratories report variants of uncertain significance (VUS)
to clinicians and/or patients? Should they reinterpret VUS in response to growing
knowledge in the field? And should patients be recontacted regarding such results? We
systematically analyzed 58 consent forms in English used in the diagnostic context to
investigate their policies for a) reporting VUS, b) reinterpreting variants, including who
should initiate this, and c) recontacting patients and the mechanisms for undertaking any
recontact. One-third (20/58) of the forms did not mention VUS in any way. Of the 38
forms that mentioned VUS, only half provided some description of what a VUS is.
Approximately one-third of forms explicitly stated that reinterpretation of variants for
clinical purposes may occur. Less than half mentioned recontact for clinical purposes,
with variation as to whether laboratories, patients or clinicians should initiate this. We
suggest that the variability in variant reporting, reinterpretation, and recontact policies
and practices revealed by our analysis may lead to diffused responsibility, which could
result in missed opportunities for patients or family members to receive a diagnosis in
response to updated variant classifications. Finally, we provide some suggestions for
ethically appropriate inclusion of policies for reporting VUS, reinterpretation, and
recontact on consent forms.
Keywords: Variants of uncertain significance; informed consent; genomics; recontact;
inductive content analysis; bioethics.
3
Introduction
A major challenge associated with the clinical implementation of high throughput next-
generation sequencing technologies (NGS), such as sequencing of exomes, genomes and
gene panels, is the large number of variants identified (1-3). Distinguishing which of these
variants affect function and are potentially causative of the phenotype of the patient, from
those which are not, is time consuming (4), and complex; even experienced laboratory
personnel have identified the classification of variants from diagnostic NGS as a real
challenge (5). Despite the growing knowledge in the field and the presence of databases
that link variants with clinical phenotypes to aid classification (e.g. ClinVar), many of
these variants remain difficult to classify as either (likely) benign or (likely) pathogenic
in relation to the genetic condition for which testing has been sought (5, 6). These variants
of uncertain significance (VUS) may be i) in genes known to be related to the clinical
question, but where there is a lack of sufficient evidence to confirm or rule out
pathogenicity, ii) in genes where the function is uncertain (yet are potentially candidate
genes) but the nature of the DNA change suggests it could affect function, or iii) in known
disease-causing genes unrelated to the clinical question (i.e. VUS unsolicited findings)
(1).
Rather than providing specific recommendations about whether VUS should be reported
or not, guidelines issued by professional bodies generally state that laboratories should
have clearly documented protocols for the reporting of VUS to clinicians (7-10).
Interviews with personnel from 24 laboratories sampled across Europe, Canada and
Australasia suggested that laboratories have variable practices when it comes to reporting
variants to clinicians. Some limit their reporting to variants that are considered to be
4
causative of the phenotype, while others will report VUS when they are in genes related
to the clinical question, or even candidate genes where the gene function is less certain
(5). There has only been one study of six purposefully sampled CLIA certified consent
forms in the USA, which identified some variation between laboratories in their policies
for reporting VUS (11).
Another issue that has emerged from the clinical use of NGS relates to the potential
responsibilities of laboratories to reinterpret VUS in response to the growing knowledge
in the field, to reissue reports to clinicians based on any revised classifications, and for
clinicians to subsequently recontact patients (12, 13). There seems to be general
agreement that there is no duty for laboratories to routinely reinterpret sequence data, nor
for clinicians to recontact patients (8, 12, 13). However, guidelines issued by EuroGentest
have suggested that if new information arises that leads specifically to the reclassification
of a variant, the laboratory is responsible for the reanalysis of data, and for reissuing a
report and contacting the referring clinician (8). The recommendations of the Canadian
College of Medical Geneticists (CCMG) suggest that patients be informed of the potential
for further interpretation, and propose reinterpretation be initiated by the referring
physician, rather than the laboratory (7). Similarly, guidance by the American College of
Medical Genetics and Genomics and the Association for Molecular Pathology
recommends health professionals should check with laboratories periodically about the
status of any VUS, yet suggests laboratories “consider proactive amendment of cases
when a variant reported with a near-definitive classification (pathogenic or benign) must
be reclassified” (6). In contrast, researchers in the UK have suggested a ‘joint venture’
model where responsibility for recontact is shared between healthcare professionals and
5
patients (14). In addition, Ayuso et al. included reinterpretation of results and patient
recontact on their proposed minimum list of information points that consent forms for
clinical whole genome sequencing should contain (15).
Some research has been undertaken seeking the views and experiences of clinicians and
patients on these issues (12-14), yet the actual policies and practices of laboratories and
clinics relating to variant reinterpretation and recontact are relatively unexplored. Only
two studies have assessed these components of consent forms as part of their broader
analysis. Both studies identified differences between the policies of laboratories, either in
who is responsible for initiating reinterpretation or in whether the possibility for recontact
was addressed (11, 16). However, these studies comprise small samples of consent forms
and, to our knowledge, there has been no systematic investigation of consent forms to
specifically explore their policies and practices for a) the reporting of VUS, b)
reinterpretation of variants, and c) patient recontact.
In order to fill this knowledge gap, we systematically analyzed 58 consent forms being
used in the genomic diagnostic context to investigate if and how they discuss VUS. In
particular we studied what they state regarding policies for a) reporting VUS, b)
reinterpreting variants, including who should initiate this, and c) recontacting patients and
the mechanisms for undertaking any such recontact.
6
Materials and methods
Search strategy
In order to identify consent forms for potential inclusion, we used two complementary
strategies. First, an online search was performed by all four researchers independently
(March - April 2016) using Google with the search string “(consent form OR informed
consent OR consent document) AND (whole exome sequencing OR whole genome
sequencing OR next generation sequencing OR genome wide sequencing)”. Researchers
reviewed at least the first 10 pages (100 entries) of the results, beyond which results were
deemed to be repetitive and no additional forms were being identified. Second, we
included additional forms that were known to the researchers to be in use in the clinical
setting but were not identified through the online search. These search strategies resulted
in a total of 224 URLs for potential inclusion in our analysis.
Following the initial searches, the content found under each URL was then assessed by
two of the researchers independently to determine if they met the following inclusion
criteria: 1) an actual consent form requiring the signature of the patient, or their
parent/guardian (i.e. not a model form, sample form, or requisition form), 2) explicitly
for high throughput sequencing (i.e. next-generation sequencing for large gene panels
(i.e. >20 genes), exome or genome sequencing), 3) for use in the clinical/diagnostic
setting, and 4) in English. Forms were excluded if their purpose was to obtain consent
purely for research purposes.
7
Data analysis
The consent forms were initially analyzed deductively using a predetermined list of
categories (e.g. VUS, unsolicited findings, etc). This list was developed by all four
researchers and based on existing literature. Data from two categories (VUS and data
reinterpretation/patient recontact) then became the focus of the analysis and inductive
content analysis was used in which categories were derived from the data, rather than pre-
determined (17-19). Data for each consent form was coded into subcategories and
compared across forms in an iterative manner. Coding was performed by DV and checked
by HCH and EN for consistency.
Results
Consent form characteristics
A total of 58 forms met our inclusion criteria. From the 58 forms, 10 were specifically
for gaining consent from adult patients, 7 for pediatric patients, and 40 for either adult or
pediatric patients, with one form unclear regarding in which patient group it was to be
used. These forms were from 40 separate laboratories/clinics (either independent
laboratories or affiliated with a hospital/medical center) from 8 different countries (Table
1). A list of these laboratories can be found in Supplementary Table 1.
The results of the inductive content analysis are reported under the following categories:
1) VUS terms and definitions, 2) reporting practices for VUS, 3) reinterpretation and
recontact. Some excerpts from the forms have been provided as examples for each
category in Table 2.
8
VUS terms and definitions
Twenty of the 58 forms that met our inclusion criteria did not mention VUS in any way.
The remaining 38 forms used a variety of terms to refer to VUS (Table 3). The most
commonly used terms included variants of/with uncertain significance (10), variants
of/with uncertain clinical significance (4), and results of uncertain significance (4). Eight
forms provided a description of what a VUS is, rather than using a specific term. Of the
38 forms that referred to VUS, 11 did not provide a definition or description to explain
what a VUS was. Eighteen forms provided an explicit definition, where the term and the
description are linked (Table 2, example 1a). For 9/38 forms, although a definition was
provided, it was not explicit in that the description was not linked to the term (Table 2,
example 1b).
Reporting practices for VUS
Forms were assessed to determine the reporting practices for VUS (Table 3). Nineteen
forms explicitly stated that they report VUS (Table 2, example 2a), with reports often
being issued to the referring clinician, rather than directly to the patient. An additional 12
forms did not explicitly state that they report VUS but reporting was implied, such as
where a form would list VUS as a possible outcome of the test (Table 2, example 2b).
The reporting practices of the remaining seven forms were unclear. Some stated their
criteria for whether a VUS is reported or not, such as whether the variant is related to the
primary clinical question (Table 3), although most forms did not specify which types of
VUS they would report. In addition, 15 forms mentioned that they may need to test family
members in order to further classify the VUS, with several also suggesting additional
information may be required (Table 2, example 2c).
9
Reinterpretation and recontact
The forms were also analyzed to determine whether they mentioned a) reinterpretation of
variants for clinical purposes, and b) recontact, which could include either the patient or
the clinician being recontacted by the laboratory, the patient recontacting the laboratory,
the clinician recontacting the patient, or the patient recontacting the clinician.
a. Reinterpretation
Of the 58 forms that met our inclusion criteria, 25 did not raise the issue of reinterpretation
of variants for clinical purposes (Table 4). Twenty-one forms referred to the idea that
reinterpretation may take place (Table 2, example 3a). Although the remaining 12 forms
did not explicitly refer to variant reinterpretation, seven mentioned the possibility that
variants might be reclassified and five mentioned the possibility of more information
coming to light in the future. Only three of the forms sought consent for reinterpretation
to be performed and for an updated report to be issued.
Of note is the variation in the ways in which the forms discussed who should initiate any
further variant reinterpretation (Table 4). Ten forms indicated that the laboratory will
initiate any subsequent variant reinterpretation, with three forms stating that the
information will be reviewed every six months (Table 2, example 3b). Six forms indicated
that the clinician needs to initiate the reinterpretation and five leave it to the patient to
initiate the reinterpretation (Table 2, example 3c).
10
b. Recontact
Twenty-three of the 58 forms mention some form of recontact for clinical purposes (Table
4). Within this group, there was again considerable variation regarding who will initiate
recontact in light of any new information (Table 4). Forms commonly indicated that the
laboratory will either recontact the clinician (8 forms), or the patient (8 forms), or they
recommended that the patient should recontact the clinician in order to check if there have
been any changes to their results (6 forms). One form stated that the clinician should
contact the laboratory and none of the forms suggested that the patient should contact the
laboratory directly. Only four of the forms sought consent to recontact patients for clinical
purposes.
Discussion
Our analysis of 58 forms used for WGS, WES, or large NGS panels shows considerable
variation in policies between laboratories/clinics in the reporting of VUS, as well as how
they address reinterpretation of variants, and patient recontact.
Variants of uncertain significance
Of note, one-third of the forms in our study did not mention VUS. In those that did, we
identified that there was some subtle variation in the terms used to refer to VUS. While
most varied in their use of the terms “uncertain” versus “unclear” and the presence or
absence of “clinical”, four of the forms referred to VUS as “results”, rather than variants.
In general, whether a VUS is named as uncertain or unclear may not make much
difference to how they are explained to patients. However, labelling a VUS as a “result”
may give the wrong impression to both the clinician and the patient that the identification
11
of this variant carries with it greater certainty or clinical significance than is warranted.
This finding is particularly troubling in the context of concerns raised by laboratory
personnel that health professionals might over-interpret the significance of VUS if they
are reported to clinicians and/or included in the medical file (5).
There was also variation in whether explicit definitions or explanations of the term VUS
(or related terminology) were provided. Roughly half of the forms in which VUS were
mentioned provided some description as to what a VUS is. While in most cases the
definition was explicit where the description was linked to the term used, in some cases
this was less explicit or a description alone was used. The concept of a VUS may be
difficult for patients (and also clinicians) to fully appreciate (20). One could argue that it
is implicit within the doctor-patient relationship that the clinician will make judgments
about what is in the patients’ best interests and therefore describing a VUS to the patient
on the consent form may not be necessary. However, it might be confusing to patients
why a finding that is not a definitive result would be listed on a report, particularly if they
ask for a copy. Listing on the consent form that a VUS is a possible outcome of the test,
and providing a description of the term which clearly states that this is not a causative
result, may help alleviate some of this confusion.
While there is no specific guidance provided by professional bodies as to whether VUS
should be reported, several guidelines suggest that laboratories should have well-
established policies addressing VUS, which need to be made clear to referring clinicians
(7-10). One way to inform clinicians of these policies, outside of continuing education
or distinct information pamphlets, is by providing information or policies in requisition
12
and/or consent forms. Yet, only approximately one-third of the forms in our study
explicitly stated that VUS would be reported. Most forms either did not mentioned VUS
at all or did not explicitly state their reporting policies for this type of finding. Also, in
many cases, it was difficult to assess which VUS would be reported as most forms did
not specify their reporting criteria. Of those that did, they would generally report VUS
when they were thought to be related to the condition for which testing was sought, which
is in line with practices reported by laboratory personnel that do report VUS (5). One
could argue that providing too much detail regarding reporting policies should be avoided
in order to simplify often already lengthy and complicated consent forms (21, 22).
However, given that reporting practices seem to vary depending on the laboratory (5), it
is important that the laboratory policy is made clear to the referring clinician so that both
they, and their patients, are aware of whether these types of findings will be returned.
Interestingly, interviews with genetic counsellors and research coordinators have
identified that although the potential results of sequencing are often a main focus of
genetic counselling sessions for WES and WGS, uncertainty of results is an aspect which
they felt is likely to be misunderstood by patients/research participants (23).
Reinterpretation and recontact
As the use of NGS for both research and clinical purposes increases, and variants that are
identified are shared on accessible databases, the status of previously unclassifiable
variants is likely to change. In fact, evidence is now mounting to suggest that reanalyzing
existing exome data increases the diagnostic yield, even as soon as 12 months after the
initial analysis (24-26). A currently unresolved 2016 lawsuit, Athena vs Williams, is
testing the legalities of this area. In this case, the genetic testing company is being sued
13
for alleged negligence based on their original classification of a variant as a VUS, which
was later reclassified by them to be “pathogenic”, meaning that the variant was thought
to affect function (27). Regardless of the outcome, it is important for laboratories,
clinicians and patients to all be aware of their own rights and responsibilities in relation
to both the reinterpretation of variants and the recontact of patients in response to changes
in variant reclassification.
In relation to data reinterpretation, a number of professional guidelines have proposed
that there is no duty for laboratories to reanalyze sequence data in response to changes in
variant databases (7, 8). Yet, there have been suggestions that it might be good practice
for a laboratory to reissue a report if a variant is reclassified (6, 8, 12, 13). Given the lack
of consensus on the issue, perhaps more important is that patients are informed whether
or not variant reinterpretation may take place. Yet our study showed that only around
one-third of forms explicitly stated that reinterpretation of variants for clinical purposes
may occur, and a large proportion did not even mention reinterpretation. Some forms
suggested that variants might be reclassified or that more information may come to light
in the future, without being more explicit as to the process involved. This suggests that
many of the forms we identified are not conforming with the minimum list of information
for inclusion suggested by Ayuso et al. (which was developed based on review of
guidelines for genetic studies and proposed that consent forms should list policies for,
among other aspects, reinterpreting results), or recommendations by the CCMG on this
point (7, 15).
14
Less than half of the forms mention recontact for clinical purposes (as opposed to research
purposes), which corresponds with a study by Fowler et al. which analyzed consent forms
from 18 laboratories in which only half of the forms they analyzed discussed the
possibility for recontact if reinterpretation of the results led to new information (16). This
again may not be in line with suggestions that recontact should be included as one of the
elements on consent forms for high-throughput genomic sequencing (15). As far as we
are aware, no legal system has explicitly endorsed a legal responsibility for healthcare
professionals to recontact patients once the care relationship has finished. Although legal
systems have approaches to deal with medical negligence and medical faults, it seems
unlikely that those would apply in this context (28). In our study, of those forms that did
mention recontact, we identified considerable variation as to whether the form nominated
the laboratory, the clinician, or the patient as responsible for initiating recontact (although
not all forms described these). Interestingly, there were a proportion of forms that
indicated that the laboratory/clinic would recontact the patient in response to new
information. This may be ineffective if the patient has changed their contact details since
their initial testing, but also inappropriate unless the laboratory/clinic also plans to
provide the patient with genetic counselling to help them understand the results. This
finding of variation in policies supports those of a study of clinical genetic services in the
UK which used surveys with healthcare professionals, and interviews with both
laboratory specialists and healthcare professionals, to show that practices relating to
recontact of patients in response to new genetic information was both very variable and
unsystematic across the board (12, 13). Both these studies, and interviews with patients,
have flagged the confusion around the delineation of responsibility for initiating recontact
as a serious challenge and a major barrier to the harmonization of practices (12-14). In
15
addition, systematic review of the literature relating to recontact has led to calls for
professional consensus and development of guidelines (29). In response to these findings,
a “joint venture” model has been proposed which would involve the responsibility for
recontact being shared between the healthcare professional and the patient (14). Although
this would circumvent issues related to patients being lost to follow up which may occur
if reinterpretation is initiated by the laboratory, the allocation of responsibility between
the patient and the healthcare professional using this model may remain unclear (14).
Indeed, although most of the patients/parents interviewed in the UK study favoured this
“joint venture” model, because they felt allowing the responsibility for recontact to rest
solely with them could lead to harm, some participants also acknowledged that any such
system working would require both better infrastructure, and better communication
between healthcare professionals and patients (30). In addition, although harmonization
in practices and adoption of this type of model might be desirable in the UK, whether this
is appropriate more broadly requires further consideration.
To our knowledge, this is the first study to systematically identify and analyze consent
forms for high-throughput diagnostic NGS in relation to what they state regarding
policies for reporting VUS, variant reinterpretation, and patient recontact, who should
initiate this reinterpretation, and how recontact might take place. Given our strategy of
including consent forms predominantly identified through online searches, and only those
in English, our data set is not designed to be representative of all consent forms being
used for diagnostic high-throughput sequencing. Our search strategy also meant that any
supplementary information located in a separate file, such as a brochure, would not have
been included. While providing additional information can be meaningful and useful to
16
those seeking it, indeed, there is a risk that many (potentially most) will not read this
information on their own. We would suggest that for now, given current consent practices,
it makes more sense for the information and consent form to be in one document.
However, importantly, the form should have a summary page which contains all of the
main points in brief, any patient choice options, and the place for the patient’s signature.
In addition, we cannot extrapolate how these forms are being used by clinicians during
the informed consent process with their patients. Reports of genetic counsellors and
research coordinators by Bernhardt et al. suggest that they tend to adjust the content of
counselling sessions, focusing less on “standard” elements of informed consent and
tailoring sessions to a given patient/research participant (23). This often results in the
genetic counsellors/researchers placing more attention on issues which are likely to be
misunderstood by patients, such as uncertainty of the results. Our knowledge in the field
would benefit from recorded consultations, or interviews with clinicians to explore the
topics of VUS and recontact further. Despite this, our analysis provides important insights
into the variation in how VUS and recontact are addressed in forms used both to as
supporting tools to guide informed consent sessions, and to document patient consent.
Based on these findings, we have provided some suggestions for ethically appropriate
inclusion of policies for reporting VUS, reinterpretation, and recontact on consent forms
in Table 5. Should genomic sequencing become offered increasingly in primary care
setting, primary care physicians may need to rely more on the information included in
consent forms than clinicians who are thoroughly trained in genetics. While the jury is
still out as to whether individual laboratories should retain the ability to determine their
own reporting practices regarding VUS, or whether we should be aiming for
harmonization of practices, it is important that the policy is made clear to the clinician
17
and patient. Whether the consent form is the best place for detailed descriptions of
reporting policies also requires further consideration.
We identified very variable policies regarding the reinterpretation of variants, and also
who is deemed responsible for the initiation of recontact. This is problematic because
diffused responsibility has the potential to lead to lack of action, which could mean a
missed opportunity for a patient and/or family member to receive a diagnosis in response
to updates in variant classification. This is particularly challenging for patients not
receiving ongoing care. More work is required to determine with whom this responsibility
should rest, and how recontact can be implemented into the infrastructure of existing
healthcare systems. Regardless of the model decided upon, it is important that the roles
and responsibilities of the laboratory, clinician, and patient are clear to all parties. The
consent form seems like an appropriate place for these to be outlined to ensure everyone
is aware of the process and to allow for a conversation with the patient to be initiated by
the clinician during the informed consent process. Of course, there are some countries
(including Belgium, among others), where written consent for clinical genetic testing is
not legally obligatory. Therefore, it is also important to incorporate specific training for
health professionals who are likely to be ordering genomic sequencing for their patients
in order to equip them with the knowledge and skills to undertake the consent process
adequately. Development of a template consent form that these health professionals could
use as a guide for such situations would also be warranted.
18
Acknowledgments
Danya Vears is a Postdoctoral Research Fellow of the Research Foundation, Flanders
(FWO). Emilia Niemiec has been supported by Erasmus Plus Joint International PhD
Programme in Law, Science and Technology Fellowship. This work was facilitated by
the COST Action IS1303 'Citizen’s Health through public-private Initiatives: Public
health, Market and Ethical perspectives’, supported by COST (European Cooperation in
Science and Technology) (http://www.cost.eu). Part of this work has been supported by
the SIENNA project, (under grant agreement No 741716) and the BBMRI-ERIC.
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Tables
Table 1. Laboratory/clinic characteristics
Laboratory/clinic characteristics No. laboratories/
clinics (N = 40)
Countries
- USA
- Germany
- The Netherlands
- Austria
- Australia
- England
- India
- Finland
26
4
3
2
2
1
1
1
Laboratory type
- Hospital/university affiliated
- Non-hospital/university affiliated
14
26
23
Table 2. Example excerpts from consent forms aThe text was corrected for word order. The original version reads: “not currently
reported in association with known a genetic…”
Category Description Excerpt from consent form Form #
1. VUS
terms and
definitions
a. Explicit
definition of
VUS
Variant with uncertain significance: Sometimes the
test will find a genetic variation that is predicted to
be important, but has not been reported or seen
before in people with your child’s condition.
4
b. Non-
explicit
definition of
VUS
Abnormalities in genes may be found that have not
been reported previously in the medical literature.
The significance of these abnormalities for the
patient or for the family will often be unclear.
54
2. Reporting
policies UF
a. Explicitly
state report
VUS
Variant with uncertain significance: Sometimes the
test will find a variation that is predicted to be
important, but has not been reported or seen before
in people with your child’s condition. Such a
variant may or may not be the cause of your child’s
symptoms, but the lab would report it as a “variant
with uncertain significance” if there is evidence
strongly suggesting that it is related to your child’s
condition.
8
b. VUS
reporting
implied
Possible outcomes of genetic testing:
Results of uncertain significance: Sometimes a
variant in a gene is found but its meaning is
unclear. In this situation, further testing of other
family members may be required. The
interpretation of a result may also alter as
knowledge of genetics improves. I may be contacted
if this occurs but the timeframe for any additional
results is variable.
42
c. Mention
testing
family
member
Further analysis may be recommended, including
testing both parents and other family members.
Detailed medical records or information from other
family members also may be needed to help clarify
results.
47
3. Reinter-
pretation
a. Reinter-
pretation
may take
place
Novel gene analysis may allow for the discovery of
genes not currently reported in association with
(a)a known genetic condition, and this may be a
pathway toward diagnosing a previously
undescribed genetic defect. However, under certain
circumstances a diagnosis will not be readily
available. Since new scientific information becomes
available on a regular basis, this could alter the
interpretation or significance of any sequence.
14
b.Laboratory
to initiate
4. Option to allow release of updated results 45
24
We may periodically review old cases when new
information is learned regarding the significance of
changes in a particular gene. If a possible
diagnosis can be made with this information we
would like to issue an updated report to the
physician who ordered your WES test. The current
schedule for this review is every six months, but is
subject to change and does NOT include a complete
review of all of your data.
c. Patient to
initiate
The test report is generated based on current
medical knowledge. A mutation that is not known to
be the cause of a genetic condition today, may be
shown to be disease-causing in a year or two. We
do not generate updated reports for the test, unless
we are requested to do so by the patient. There is a
fee associated with providing an updated report.
5
25
Table 3. Terms used to describe variants of uncertain significance and reporting
practices aTerm stated and then followed immediately by a description of a VUS bTerm used as part of a consent statement
Mention of variants of uncertain significance No. of forms
N=58
Terms used
- None
- Variants of/with uncertain significance
- Variants of/with uncertain clinical significance
- Results of uncertain significance
- Results of uncertain clinical significance
- Variants of unclear clinical significance
- Variants of unclear significance
- Changes with uncertain significance
- Variants of unknown clinical significance
- Variants of unknown sig. + gene of unknown sig.
- Uncertaina
- Unclear findingsb
- Varianta
- Only provide a description
20
10
4
4
1
3
1
1
1
1
2
1
1
8
Reporting practices
- Explicitly report VUS
- Reporting of VUS implied
- Unclear whether report VUS
- Provide criteria for reporting VUS
o It is related to the primary clinical concern
o There is evidence strongly suggesting related to condition
o New variants highly likely to cause primary condition if
the variants are in genes known to cause primary
condition
o Only if a definite causative variant is not identified
19
12
7
8
2
3
2
1
26
Table 4. Mention of reinterpretation and recontact for clinical purposes
a One laboratory will only perform reinterpretation if the patient meets with a genetic
counselor and signs new consent.
b One laboratory will honor reinterpretation for up to 24 months.
c Three of these forms state they will review the data every six months, although this
does not include a complete review of the data
Mention of reinterpretation and recontact No. of forms
Reinterpretation discussion
- Do not mention reinterpretation for clinical purposes
- Mention reinterpretation for clinical purposes
- Mention possibility of variant reclassification
- Mention possibility of more information in the future
Reinterpretation initiation
- Laboratory will generate a new report if initiated by patienta
- Clinician needs to initiate reinterpretationb
- Laboratory will initiate reinterpretation
25
21
7
5
5
6
10
Recontact discussion
- Do not mention recontact for clinical purposes
- Mention recontact for clinical purposes
Recontact initiation
- Laboratory will contact/issue new report to clinicianc
- Laboratory will recontact patient
- Patient told to recontact clinician
- Clinician told to recontact laboratory
35
23
8
8
6
1
27
Table 5. Suggestions for inclusion of policies for reporting VUS, reinterpretation,
and recontact on consent forms
1. Informed consent forms should clearly state the policy of the laboratory/clinic for
reporting of VUS so that both the clinician and the patient are aware of what will
be returned following testing.
2. Given the different types of VUS that may or may not be reported, a description of
what a VUS is may help clinicians and patients better understand the reporting
policies of the clinician/laboratory.
3. The reinterpretation policy of the laboratory/clinic should be clearly stated on the
consent form, including whether reinterpretation is routinely performed by the
laboratory, or if it can be requested, and by whom (i.e. the clinician or the patient).
4. The recontact policy of the laboratory/clinic should also be clearly stated on the
consent form, including whether there will be any recontact in response to any
changes in the status of variants, and who will be recontacted by the laboratory (i.e.
the clinician or the patient).